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Lysosomal damage drives mitochondrial proteome remodelling and reprograms macrophage immunometabolism

Lookup NU author(s): Dr Tiaan Heunis, Professor Matthias TrostORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2022, The Author(s).Transient lysosomal damage after infection with cytosolic pathogens or silica crystals uptake results in protease leakage. Whether limited leakage of lysosomal contents into the cytosol affects the function of cytoplasmic organelles is unknown. Here, we show that sterile and non-sterile lysosomal damage triggers a cell death independent proteolytic remodelling of the mitochondrial proteome in macrophages. Mitochondrial metabolic reprogramming required leakage of lysosomal cathepsins and was independent of mitophagy, mitoproteases and proteasome degradation. In an in vivo mouse model of endomembrane damage, live lung macrophages that internalised crystals displayed impaired mitochondrial function. Single-cell RNA-sequencing revealed that lysosomal damage skewed metabolic and immune responses in alveolar macrophages subsets with increased lysosomal content. Functionally, drug modulation of macrophage metabolism impacted host responses to Mycobacterium tuberculosis infection in an endomembrane damage dependent way. This work uncovers an inter-organelle communication pathway, providing a general mechanism by which macrophages undergo mitochondrial metabolic reprograming after endomembrane damage.

Publication metadata

Author(s): Bussi C, Heunis T, Pellegrino E, Bernard EM, Bah N, Dos Santos MS, Santucci P, Aylan B, Rodgers A, Fearns A, Mitschke J, Moore C, MacRae JI, Greco M, Reinheckel T, Trost M, Gutierrez MG

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2022

Volume: 13

Issue: 1

Online publication date: 28/11/2022

Acceptance date: 31/10/2022

Date deposited: 23/06/2023

ISSN (electronic): 2041-1723

Publisher: Nature Research


DOI: 10.1038/s41467-022-34632-8

PubMed id: 36443305


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Funder referenceFunder name
The Francis Crick Institute